Untersuchung der Dopaminrezeptor- sowie Hypocretin-Gen-Polymorphismen bei Parkinsin-Patienten mit "Schlafattacken"

Idiopathic Parkinson’s disease (PD) is a neurodegenerative disorder of unclear cause. PD is clinically characterized by “cardinal signs”: resting tremor, rigidity, and bradykinesia. The cause of the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and the consequent depletion of dopamine in its striatal projections is unknown. Sleep disorders and daytime sleepiness are frequent findings in patients with PD. However, "sleep attacks" in PD patients taking the non-ergoline dopamine agonists (DA) pramipexole (PPX) and ropinirole (ROP) have been described only in 1999. "Sleep attacks" has recently been defined as abrupt episodes of unplanned sleep during activities of daily living where they are not expected to occur (e.g. speaking, eating, or driving). These episodes may be preceded by somnolence and last from a few minutes to several hours. "Sleep attacks" in the nine initially reported cases occurred at the steering wheel and caused car accidents. In the meantime, it has become evident that "sleep attacks" can be associated with any dopaminergic medication. Although dopaminergic agents have been known to induce somnolence for a long time, the etiology of this side effect and particularly of "sleep attacks" is still unknown. Since non-ergoline DA have a negligible affinity to the dopamine D1 receptor family (i.e., the D1 and D5 receptor), we hypothesized that SOS may be associated with an alteration of dopaminergic transmission involving a member of the dopamine D2 receptor family. Therefore this study was performed investigating the distribution of previously identified polymorphisms in the family of dopamine D2 receptor genes (DRD2, DRD3, DRD4) in PD patients with and without SOS and/or daytime sleepiness. Here we examined the Taq IA polymorphism in the DRD2 gene, the Msc I polymorphism in the DRD3 gene, and a tandem duplication polymorphism in the DRD4 gene. Narcolepsy is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis and usually begins during adolescence. Hypocretins (HCRT) play a major role in the pathophysiology of narcolepsy. Human narcolepsy is probably caused by deficient HCRT neurotransmission in the lateral hypothalamus. Animal models showed narcolepsy syndromes to be caused by mutations in the hypocretinergic system. In humans, HCRT-1 is almost undetectable in the cerebrospinal fluid (CSF), and narcolepsy pathogenesis appears to be multifactorial and triggered by genetic and environmental factors. Neuropathologic studies demonstrated an almost complete loss of HCRT mRNA and peptides in human narcoleptic brains. We therefore hypothesized that the HCRT system may also be involved in the pathogenesis of SOS in PD and investigated the distribution of the previously described preprohypocretin (-909C/T), (-22C/T), and (-20C/A) polymorphisms in PD patients with and without SOS. In summary, this study demonstrates a significant association between the DRD2 variant allele A2 and SOS in PD patients. Furthermore, our results show a significant association between the (-909C/T) preprohypocretin polymorphism and SOS in PD.